Identifying Risk Variants for Alzheimer's Disease using Cerebrospinal Fluid Tau Levels
Cerebrospinal fluid (CSF) tau and beta amyloid (Aβ) levels have been shown to be good biomarkers for disease and endophenotypes when conducting genetic studies of Alzheimer's Disease (AD) (1). Before delving into the largest GWAS (Genome Wide Associated Study) for CSF tau/phosphorylated tau (ptau) levels (n = 1,269), time should be taken to outline a few key concepts. It has been shown that CSF tau, ptau and Aβ levels are higher in AD patients than in healthy patients (1). It has also been shown that changes in CSF tau, ptau and Aβ levels are linked to genetic variants that increase the risk of AD (1). These variants include mutations in: APP - amyloid precursor protein; major component of beta amyloid plaques (2). PSEN1 - a member of the presenilin family, this gene codes for the PS1 enzyme which when mutated leads to increased production of Aβ (3). PSEN2 - another member of the presenilin protein family, it codes for PS2 which may be a catalytic subunit of the gamma secretase complex. Mutations in PSEN2 lead to increased Aβ production (4). ApoE - apolipoprotein E is a major constituent of very low density lipoproteins (VLDLs) and is involved in lipid transport, mutations in this protein lead to increased risk of AD (5). As would be expected, levels if CSF ptau correlate with levels of ptau in the brain and with the number of neurofibrillary tangles (NFTs) present (1). High CSF ptau levels also correspond with neuronal loss, cognitive decline and eventual development of AD (1). Building on this information, this GWAS was done for CSF tau and ptau using lumbar puncture (LP) samples from four different institutions. Along with the 'raw' information provided by the samples (levels of tau, ptau and Aβ etc.), the clinical dementia rating (CDR) of each patient at date of LP was reported (1). Their population was divided into 687 healthy elderly patients and 591 with an AD diagnosis. Their objective was to identify genes upregulated with high levels of CSF tau, ptau and Aβ. How do ApoE Variants affect Tau and ptau levels? Several hypotheses postulate that ApoE may indirectly promote AD through an Aβ-dependent mechanism (1 ). Given this hypothesis, you would expect to see a direct association of APP but not ApoE with AD. However, when analyzing the data, Cruchaga et al. (2013), found that several ApoE SNPs (single nucleotide polymorhisms) were significantly associated with tau and ptau. Using CSF Aβ thresholds of 500 pg/ml (for Knight-ADRC samples) and 192 pg/ml (for ADNI samples) to denote high and low levels of Aβ corresponding to AD and preclinical AD cases, they found a significant relationship between SNPs rs9877502 (SNR-1; intragenic) and rs514716 (GLIS3; intron) on chromosomes 3 and 9 and tau and ptau levels (respectively) which was more pronounced in the high Aβ group (1). Taken as a whole, their data suggests that the association of ApoE with tau and ptau levels is not entirely dependent on the formation of Aβ plaques. New SNPs Associated with AD Besides the SNPs associated with AD that were previously identified, this study found SNPs in three other loci, two of which were significantly associated with CSF tau and ptau levels. SNPs were found within the 3q28 locus. The genes in this locus are GEMC1, OSTN along with noncoding RNA SNAR-I, IL6RAP, UTS2D and CCDC50 (1). GEMC1 - codes for geminin coiled-coil containing protein 1. This portein regulates DNA replication by initiating recruitment of replication factors to origins of replication (6). OSTN - codes for osteocrin which may modulate osteoblastic differentiation and has also been linked to glucose metabolism (7). All of these genes are upregulated in the brain and are involved in neuronal synaptogenesis (the formation of synapses) (1). Within the 3q28 locus, 34 SNPs were found in transciption factor binding sites and transcription factor matrix sites (1). Changes at these SNPs could influence the expression levels of the genes located in 3q28 and contribute to AD. The other locus strongly associated with elevated tau/ptau CSF levels, was 6p21.1 which contains genes for the TREM (triggering receptor on myeloid cells) family that play a role in immune response (1,8). SNPs were found in the regulatory region for TREM family genes and FOXP4 (1). Changes in these SNPs may contribute to AD. TREM2 was expressed at higher levels in AD samples compared to the controls (1). What does all this mean? The authors were able to show that using large volumes of data in genetic studies of disease endopheotypes can lead to the identification of risk loci. Based on the identifications in this study, the impact of the implicated genes could be tested in a 'wet' lab environment. In essence, this study provides a guide for further study of the implicated genes. References 1. Cruchaga C'', et al.'' (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78(2):256-268. 2. Stern J (2013) Alzheimer's Disease. Wikia 3. Wikipedia (2013) PSEN1, http://en.wikipedia.org/wiki/PSEN1 4. Genetics Home Reference (2013) PSEN2, http://ghr.nlm.nih.gov/gene/PSEN2 5. Genetics Home Reference (2013) APOE, http://ghr.nlm.nih.gov/gene/APOE 6. GeneCards (2013) GEMC1. Weizmann Institute of Science ''http://bioinformatics.mdanderson.org/genecards/cgi-bin/carddisp.pl?gene=GEMC1 7. GeneCards (2013) OSTN. ''Weizmann Institute of Science http://www.genecards.org/cgi-bin/carddisp.pl?gene=OSTN 8. Sharif O & Knapp S (2008) From expression to signaling: roles of TREM-1 and TREM-2 in innate immunity and bacterial infection. Immunobiology 213(9-10):701-713\